We search for mutations responsible for inherited neurological and psychiatric disorders. The phenotypic heterogeneity seen within these inherited disorders can be due to involvement of multiple genes or a consequence of different mutations in a single gene, each affecting protein activity and influencing the processing, compartmentalization and/or stability of the protein. In the case of genetic disorders where a protein abnormality has been identified (such as Gaucher disease), southern analysis and polymerase chain amplification is used to identify mutations that occur in non-neuronopathic and neuronopathic phenotypes. The molecular mechanisms leading to nervous system involvement in these disorders are also studied. The results of this research should provide a molecular basis for diagnosis and formulation of additional therapeutic strategies for these inherited disorders. Genes that may be involved in neuropsychiatric disorders, such as those for neurotransmitter biosynthesis (for example, human tyrosine hydroxylase and tryptophan hydroxylase) and receptors (for example, human GABA receptor) have been isolated. Using DNA markers spaced at 10-20 centiMorgan intervals, we are performing linkage analysis and attempting to identify the gene loci responsible for bipolar illness in an Amish pedigree.